Systems and methods for avoiding neural stimulation habituation

ABSTRACT

An embodiment relates to a method for delivering a vagal stimulation therapy to a vagus nerve, including delivering a neural stimulation signal to non-selectively stimulate both afferent axons and efferent axons in the vagus nerve according to a predetermined schedule for the vagal stimulation therapy, and selecting a value for at least one parameter for the predetermined schedule for the vagal stimulation therapy to control the neural stimulation therapy to avoid physiological habituation to the vagal stimulation therapy. The parameter(s) include at least one parameter selected from the group of parameters consisting of a predetermined therapy duration parameter for a predetermined therapy period, and a predetermined intermittent neural stimulation parameter associated with on/off timing for the intermittent neural stimulation parameter.

CLAIM OF PRIORITY

This application is a continuation of and claims the benefit of priorityunder 35 U.S.C. §120 to U.S. patent application Ser. No. 12/231,372,filed on Sep. 2, 2008, which claims the benefit under 35 U.S.C. 119(e)of U.S. Provisional Patent Application Ser. No. 60/972,154, filed onSep. 13, 2007, which are both incorporated herein by reference in theirentirety.

TECHNICAL FIELD

This application relates generally to medical devices and, moreparticularly, to systems, devices and methods for delivering neuralstimulation and avoiding physiological habituation to the neuralstimulation.

BACKGROUND

Neural stimulation has been proposed as a therapy for a number ofconditions. Examples of neural stimulation therapies include neuralstimulation therapies for respiratory problems such a sleep disorderedbreathing, blood pressure control such as to treat hypertension, cardiacrhythm management, myocardial infarction and ischemia, heart failure,epilepsy, depression, pain, migraines, eating disorders and obesity.Neural stimulation therapies can involve intermittent neuralstimulation.

At the 2006 European Society of Cardiology meeting, De Ferrari et al.showed preliminary results from a study of chronic vagal nervestimulation study in heart failure patients, where Class III heartfailure patients were provided six months of therapy, uncontrolled,using an implantable vagal stimulator designed to reduce heart rate. Thestimulator delivered selective efferent stimulation to the vagus nerve,targeted to slow the heart rate, and used sensed heart rate as anegative feedback therapy control that delivers vagus nerve stimulationwhen the heart rate is elevated and shuts off vagus nerve stimulationwhen the heart rate falls below a threshold. The stimulator continuouslydelivered vagus nerve stimulation when the heart rate is elevated, andsynchronized the vagus nerve stimulation with the heart rate. The dataindicated improvement over the first three months with regression overthe next three months. De Ferrari et al. hypothesized that theregression was due to the severity and unstoppable progression of theunderlying disease.

SUMMARY

In addition or alternative to the hypothesis that the regression is dueto the progression of the underlying disease in human studies, anotherpossible explanation or contributing factor for the regression observedin the preliminary results is physiological habituation to the vagusnerve stimulation therapy delivered in the study. The present subjectmatter is based on a developed neural stimulator prototype used inmultiple animal studies that does not exhibit the regression illustratedin the presented results of the De Ferrari et al. study.

An embodiment relates to a method for delivering a vagal stimulationtherapy to a vagus nerve, including delivering a neural stimulationsignal to non-selectively stimulate both afferent axons and efferentaxons in the vagus nerve according to a predetermined schedule for thevagal stimulation therapy, and selecting a value for at least oneparameter for the predetermined schedule for the vagal stimulationtherapy to control the neural stimulation therapy to avoid physiologicalhabituation to the vagal stimulation therapy. The parameter(s) includeat least one parameter selected from the group of parameters consistingof a predetermined therapy duration parameter for a predeterminedtherapy period, and a predetermined intermittent neural stimulationparameter associated with on/off timing for the intermittent neuralstimulation parameter.

An embodiment relates to a method including, using an external device toprogram at least one neural stimulation schedule parameter forcontrolling a scheduled neural stimulation therapy of an implantableneural stimulator, and delivering the scheduled neural stimulationtherapy using the implantable neural stimulator, including deliveringnon-selective neural stimulation to both afferent and efferent axons ofa vagus nerve. The neural stimulation schedule parameter(s) includes atleast one parameter with a value selected to control the neuralstimulation therapy to avoid physiological habituation to the vagalstimulation therapy. The neural stimulation schedule parameter(s)includes at least one parameter selected from the group of parametersconsisting of at least one predetermined therapy duration parameter fora predetermined therapy period, and at least one predeterminedintermittent neural stimulation parameter associated with on/off timingfor the intermittent neural stimulation parameter.

A neural stimulator embodiment includes a neural stimulation deliverysystem and a controller operationally connected to the neuralstimulation delivery system. The neural stimulation delivery system isadapted to non-selectively stimulate both afferent axons and efferentaxons in a vagus nerve. The controller includes a neural stimulationscheduler to control neural stimulation from the neural stimulationsystem according to a predetermined schedule. The predetermined scheduleincludes at least one parameter with a value selected to avoidphysiological habituation to the neural stimulation. The parameter(s)include at least one parameter selected from the group of parametersconsisting of a predetermined therapy duration parameter for apredetermined therapy period, and a predetermined intermittent neuralstimulation parameter associated with on/off timing for the intermittentneural stimulation parameter.

This Summary is an overview of some of the teachings of the presentapplication and not intended to be an exclusive or exhaustive treatmentof the present subject matter. Further details about the present subjectmatter are found in the detailed description and appended claims. Otheraspects will be apparent to persons skilled in the art upon reading andunderstanding the following detailed description and viewing thedrawings that form a part thereof, each of which are not to be taken ina limiting sense. The scope of the present invention is defined by theappended claims and their equivalents.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 illustrates a neural stimulator device embodiment. Theillustrated device 100 is adapted to deliver chronic neural stimulation.

FIG. 2 illustrates an example of variable stimulation periods (SP) andduty cycles (DC).

FIG. 3 illustrates an example of constant stimulation periods (SP) andduty cycles (DC).

FIG. 4 illustrates baroreflex adaptation using a relationship betweencarotid sinus pressure, sympathetic nerve activity (SNA) and meanarterial pressure (MAP).

FIG. 5 illustrates a method to periodically modulate neural stimulation,according to various embodiments of the present subject matter.

FIGS. 6 and 7 show example waveforms as would be produced by recordingthe potential between stimulation electrodes.

FIGS. 8 and 9 show example waveforms as would be produced by acapacitive discharge pulse output circuit.

FIGS. 10 and 11 illustrate embodiments of circuitry for deliveringstimulation pulse trains.

FIG. 12 illustrates a system including an implantable medical device(IMD) 1238 and an external system or device, according to variousembodiments of the present subject matter.

FIG. 13 illustrates a system including an external device, animplantable neural stimulator (NS) device and an implantable cardiacrhythm management (CRM) device, according to various embodiments of thepresent subject matter.

FIG. 14 illustrates a system embodiment in which an implantable medicaldevice (IMD) is placed subcutaneously or submuscularly in a patient'schest with lead(s) positioned to stimulate a vagus nerve.

FIG. 15 illustrates a system embodiment that includes an implantablemedical device (IMD) with satellite electrode(s) positioned to stimulateat least one neural target.

FIG. 16 illustrates an implantable medical device (IMD) having a neuralstimulation (NS) component and a cardiac rhythm management (CRM)component according to various embodiments of the present subjectmatter.

FIG. 17 shows a system diagram of an embodiment of amicroprocessor-based implantable device, according to variousembodiments.

FIG. 18 illustrates an IMD placed subcutaneously or submuscularly in apatient's chest with lead(s) positioned to provide a CRM therapy to aheart, and with lead(s) positioned to stimulate and/or inhibit neuraltraffic at a neural target, such as a vagus nerve, according to variousembodiments.

FIG. 19 illustrates an IMD with lead(s) positioned to provide a CRMtherapy to a heart, and with satellite transducers positioned tostimulate/inhibit a neural target such as a vagus nerve, according tovarious embodiments.

FIG. 20 is a block diagram illustrating an embodiment of an externalsystem.

DETAILED DESCRIPTION

The following detailed description of the present subject matter refersto the accompanying drawings which show, by way of illustration,specific aspects and embodiments in which the present subject matter maybe practiced. These embodiments are described in sufficient detail toenable those skilled in the art to practice the present subject matter.Other embodiments may be utilized and structural, logical, andelectrical changes may be made without departing from the scope of thepresent subject matter. References to “an”, “one”, or “various”embodiments in this disclosure are not necessarily to the sameembodiment, and such references contemplate more than one embodiment.The following detailed description is, therefore, not to be taken in alimiting sense, and the scope is defined only by the appended claims,along with the full scope of legal equivalents to which such claims areentitled.

An embodiment of the present subject matter provides vagus nervestimulation for heart failure therapy, where the vagus nerve stimulationtherapy avoids or prevents habituation to the therapy and maintains theefficacy of the vagus nerve stimulation therapy. According to variousembodiments, the heart failure therapy (or other vagus nerve stimulationtherapy) of the present subject matter provides non-selectivestimulation of the vagus nerve, such that both efferent and afferentvagal axons are stimulated, and delivers the stimulation according to astimulation schedule independent of the sensed heart rate. The afferentstimulation may be important in avoiding the habituation effect.Stimulation of the afferent axons in the vagus nerve stimulates abaroreflex. The naturally occurring baroreflex mechanism involves aneural pathway from an afferent neural pathway to the central nervoussystem through an efferent neural pathway to nerves that controldilation/constriction of the blood vessel. Sensory nerve endings thatare sensitive to pressure, referred to as baroreceptors, function as areceptor for the baroreflex mechanism. If the central nervous systemsenses an increase in blood pressure from sensory nerve endingssensitive to pressure through an afferent pathway, the central nervoussystem controls nerves to, among other things, dilate blood vessels toreduce pressure.

It is believed that neural stimulation delivered on demand (duringperiods of elevated heart rate as delivered by the stimulator in theFarrari et al. study) will be primarily delivered while the patient isawake, as the patient likely has lowered heart rate during sleep. Asheart failure reverses with the delivery of therapy, the heart rate willslow. It is believed that a heart failure therapy involving on-demand,selective efferent vagus nerve stimulation targeted to slow heart ratedoes not avoid physiological habituation to the efferent stimulation ofthe vagus nerve. Further, the negative feedback control based on sensedheart rate for the efferent vagus nerve stimulation causes the heartfailure therapy to be withdrawn (the duration of stimulation over aperiod of time becomes less) as the heart failure reverses with thedelivery of therapy. Rather, some embodiments of the present subjectmatter chronically deliver intermittent or continuous stimulationaccording to a schedule that delivers the vagus nerve stimulation for atleast a minimum time per day. For example, intermittent stimulation,even at the same 24-hour average duty cycle, would be designed to bedelivered for at least a specified number of hours per day.

It is believed that prolonged neural stimulation, such as a duty cycleover 50%, may result in physiological adaptation to the stimulation.Some embodiments of the present subject matter limit the duty cycle ofcontinuous neural stimulation delivered during a scheduled neuralstimulation session. For example, an embodiment limits the duty cycle tobelow 50%. Some embodiments limit the stimulation period for theintermittent stimulation cycle. For example, some embodiments limit thestimulation period to a time under five minutes, such that a new neuralstimulation train will begin within five minutes of the previous neuralstimulation train. Some embodiments, for example, deliver neuralstimulation on the order of ten seconds per minute (duty cycle≈17%;neural stimulation period≈1 minute; duration of neural stimulationtrain≈ten seconds).

Provided below, for the benefit of the reader, is a brief discussion ofphysiology and therapies. The disclosure continues with a discussion ofvarious device, system and method embodiments.

Physiology

The automatic nervous system (ANS) regulates “involuntary” organs, whilethe contraction of voluntary (skeletal) muscles is controlled by somaticmotor nerves. Examples of involuntary organs include respiratory anddigestive organs, and also include blood vessels and the heart. Often,the ANS functions in an involuntary, reflexive manner to regulateglands, to regulate muscles in the skin, eye, stomach, intestines andbladder, and to regulate cardiac muscle and the muscle around bloodvessels, for example.

The ANS includes the sympathetic nervous system and the parasympatheticnervous system. The sympathetic nervous system is affiliated with stressand the “fight or flight response” to emergencies. Among other effects,the “fight or flight response” increases blood pressure and heart rateto increase skeletal muscle blood flow, and decreases digestion toprovide the energy for “fighting or fleeing.” The parasympatheticnervous system is affiliated with relaxation and the “rest and digestresponse” which, among other effects, decreases blood pressure and heartrate, and increases digestion to conserve energy. The ANS maintainsnormal internal function and works with the somatic nervous system.

The heart rate and force is increased when the sympathetic nervoussystem is stimulated, and is decreased when the sympathetic nervoussystem is inhibited (the parasympathetic nervous system is stimulated).An afferent nerve conveys impulses toward a nerve center. An efferentnerve conveys impulses away from a nerve center.

Stimulating the sympathetic and parasympathetic nervous systems can haveeffects other than heart rate and blood pressure. For example,stimulating the sympathetic nervous system dilates the pupil, reducessaliva and mucus production, relaxes the bronchial muscle, reduces thesuccessive waves of involuntary contraction (peristalsis) of the stomachand the motility of the stomach, increases the conversion of glycogen toglucose by the liver, decreases urine secretion by the kidneys, andrelaxes the wall and closes the sphincter of the bladder. Stimulatingthe parasympathetic nervous system (inhibiting the sympathetic nervoussystem) constricts the pupil, increases saliva and mucus production,contracts the bronchial muscle, increases secretions and motility in thestomach and large intestine, increases digestion in the small intention,increases urine secretion, and contracts the wall and relaxes thesphincter of the bladder. The functions associated with the sympatheticand parasympathetic nervous systems are many and can be complexlyintegrated with each other.

Vagal modulation may be used to treat a variety of cardiovasculardisorders, including heart failure, post-MI remodeling, andhypertension. These conditions are briefly described below.

Heart failure refers to a clinical syndrome in which cardiac functioncauses a below normal cardiac output that can fall below a leveladequate to meet the metabolic demand of peripheral tissues. Heartfailure may present itself as congestive heart failure (CHF) due to theaccompanying venous and pulmonary congestion. Heart failure can be dueto a variety of etiologies such as ischemic heart disease.

Hypertension is a cause of heart disease and other related cardiacco-morbidities. Hypertension occurs when blood vessels constrict. As aresult, the heart works harder to maintain flow at a higher bloodpressure, which can contribute to heart failure. Hypertension generallyrelates to high blood pressure, such as a transitory or sustainedelevation of systemic arterial blood pressure to a level that is likelyto induce cardiovascular damage or other adverse consequences.Hypertension has been arbitrarily defined as a systolic blood pressureabove 140 mm Hg or a diastolic blood pressure above 90 mm Hg.Consequences of uncontrolled hypertension include, but are not limitedto, retinal vascular disease and stroke, left ventricular hypertrophyand failure, myocardial infarction, dissecting aneurysm, andrenovascular disease.

Cardiac remodeling refers to a complex remodeling process of theventricles that involves structural, biochemical, neurohormonal, andelectrophysiologic factors, which can result following a myocardialinfarction (MI) or other cause of decreased cardiac output. Ventricularremodeling is triggered by a physiological compensatory mechanism thatacts to increase cardiac output due to so-called backward failure whichincreases the diastolic filling pressure of the ventricles and therebyincreases the so-called preload (i.e., the degree to which theventricles are stretched by the volume of blood in the ventricles at theend of diastole). An increase in preload causes an increase in strokevolume during systole, a phenomena known as the Frank-Starlingprinciple. When the ventricles are stretched due to the increasedpreload over a period of time, however, the ventricles become dilated.The enlargement of the ventricular volume causes increased ventricularwall stress at a given systolic pressure. Along with the increasedpressure-volume work done by the ventricle, this acts as a stimulus forhypertrophy of the ventricular myocardium. The disadvantage ofdilatation is the extra workload imposed on normal, residual myocardiumand the increase in wall tension (Laplace's Law) which represent thestimulus for hypertrophy. If hypertrophy is not adequate to matchincreased tension, a vicious cycle ensues which causes further andprogressive dilatation. As the heart begins to dilate, afferentbaroreceptor and cardiopulmonary receptor signals are sent to thevasomotor central nervous system control center, which responds withhormonal secretion and sympathetic discharge. It is the combination ofhemodynamic, sympathetic nervous system and hormonal alterations (suchas presence or absence of angiotensin converting enzyme (ACE) activity)that ultimately account for the deleterious alterations in cellstructure involved in ventricular remodeling. The sustained stressescausing hypertrophy induce apoptosis (i.e., programmed cell death) ofcardiac muscle cells and eventual wall thinning which causes furtherdeterioration in cardiac function. Thus, although ventricular dilationand hypertrophy may at first be compensatory and increase cardiacoutput, the processes ultimately result in both systolic and diastolicdysfunction. It has been shown that the extent of ventricular remodelingis positively correlated with increased mortality in post-MI and heartfailure patients.

Therapies

The present subject matter relates to systems, devices and methods forproviding neural stimulation, such as vagus nerve stimulation, andfurther relates to delivering neural stimulation therapy (NST) withparameter(s) selected to avoid habituation. Various embodiments providea stand-alone device, either externally or internally, to provide neuralstimulation therapy. The present subject matter can be implemented incardiac applications for neural stimulation or in non-cardiacapplications for neural stimulation where a diverse nerve (such as thevagus nerve) is stimulated. For example, the present subject matter maydeliver anti-remodeling therapy through neural stimulation as part of apost-MI or heart failure therapy. The present subject matter may also beimplemented in non-cardiac applications, such as in therapies to treatepilepsy, depression, pain, obesity, hypertension, sleep disorders, andneuropsychiatric disorders. Various embodiments provide systems ordevices that integrate neural stimulation with one or more othertherapies, such as bradycardia pacing, anti-tachycardia therapy,remodeling therapy, and the like.

Neural Stimulation Therapies

Examples of neural stimulation therapies include neural stimulationtherapies for respiratory problems such a sleep disordered breathing,for blood pressure control such as to treat hypertension, for cardiacrhythm management, for myocardial infarction and ischemia, for heartfailure, for epilepsy, for depression, for pain, for migraines and foreating disorders and obesity. Many proposed neural stimulation therapiesinclude stimulation of the vagus nerve. This listing of other neuralstimulation therapies is not intended to be an exhaustive listing.Neural stimulation can be provided using electrical, acoustic,ultrasound, light, and magnetic therapies. Electrical neural stimulationcan be delivered using any of a nerve cuff, intravascularly-fed lead, ortranscutaneous electrodes.

A therapy embodiment involves preventing and/or treating ventricularremodeling. Activity of the autonomic nervous system is at least partlyresponsible for the ventricular remodeling which occurs as a consequenceof an MI or due to heart failure. It has been demonstrated thatremodeling can be affected by pharmacological intervention with the useof, for example, ACE inhibitors and beta-blockers. Pharmacologicaltreatment carries with it the risk of side effects, however, and it isalso difficult to modulate the effects of drugs in a precise manner.Embodiments of the present subject matter employ electrostimulatorymeans to modulate autonomic activity, referred to as anti-remodelingtherapy or ART. When delivered in conjunction with ventricularresynchronization pacing, also referred to as remodeling control therapy(RCT), such modulation of autonomic activity may act synergistically toreverse or prevent cardiac remodeling.

One neural stimulation therapy embodiment involves treating hypertensionby stimulating the baroreflex for sustained periods of time sufficientto reduce hypertension. The baroreflex is a reflex that can be triggeredby stimulation of a baroreceptor or an afferent nerve trunk. Baroreflexneural targets include any sensor of pressure changes (e.g. sensorynerve endings that function as a baroreceptor) that is sensitive tostretching of the wall resulting from increased pressure from within,and that functions as the receptor of the central reflex mechanism thattends to reduce that pressure. Baroreflex neural targets also includeneural pathways extending from the baroreceptors. Examples of nervetrunks that can serve as baroreflex neural targets include the vagus,aortic and carotid nerves.

Myocardial Stimulation Therapies

Various neural stimulation therapies can be integrated with variousmyocardial stimulation therapies. The integration of therapies may havea synergistic effect. Therapies can be synchronized with each other, andsensed data can be shared between the therapies. A myocardialstimulation therapy provides a cardiac therapy using electricalstimulation of the myocardium. Some examples of myocardial stimulationtherapies are provided below.

A pacemaker is a device which paces the heart with timed pacing pulses,most commonly for the treatment of bradycardia where the ventricularrate is too slow. If functioning properly, the pacemaker makes up forthe heart's inability to pace itself at an appropriate rhythm in orderto meet metabolic demand by enforcing a minimum heart rate. Implantabledevices have also been developed that affect the manner and degree towhich the heart chambers contract during a cardiac cycle in order topromote the efficient pumping of blood. The heart pumps more effectivelywhen the chambers contract in a coordinated manner, a result normallyprovided by the specialized conduction pathways in both the atria andthe ventricles that enable the rapid conduction of excitation (i.e.,depolarization) throughout the myocardium. These pathways conductexcitatory impulses from the sino-atrial node to the atrial myocardium,to the atrio-ventricular node, and thence to the ventricular myocardiumto result in a coordinated contraction of both atria and bothventricles. This both synchronizes the contractions of the muscle fibersof each chamber and synchronizes the contraction of each atrium orventricle with the contralateral atrium or ventricle. Without thesynchronization afforded by the normally functioning specializedconduction pathways, the heart's pumping efficiency is greatlydiminished. Pathology of these conduction pathways and otherinter-ventricular or intra-ventricular conduction deficits can be acausative factor in heart failure, which refers to a clinical syndromein which an abnormality of cardiac function causes cardiac output tofall below a level adequate to meet the metabolic demand of peripheraltissues. In order to treat these problems, implantable cardiac deviceshave been developed that provide appropriately timed electricalstimulation to one or more heart chambers in an attempt to improve thecoordination of atrial and/or ventricular contractions, termed cardiacresynchronization therapy (CRT). Ventricular resynchronization is usefulin treating heart failure because, although not directly inotropic,resynchronization can result in a more coordinated contraction of theventricles with improved pumping efficiency and increased cardiacoutput. Currently, a common form of CRT applies stimulation pulses toboth ventricles, either simultaneously or separated by a specifiedbiventricular offset interval, and after a specified atrio-ventriculardelay interval with respect to the detection of an intrinsic atrialcontraction or delivery of an atrial pace.

CRT can be beneficial in reducing the deleterious ventricular remodelingwhich can occur in post-MI and heart failure patients. Presumably, thisoccurs as a result of changes in the distribution of wall stressexperienced by the ventricles during the cardiac pumping cycle when CRTis applied. The degree to which a heart muscle fiber is stretched beforeit contracts is termed the preload, and the maximum tension and velocityof shortening of a muscle fiber increases with increasing preload. Whena myocardial region contracts late relative to other regions, thecontraction of those opposing regions stretches the later contractingregion and increases the preload. The degree of tension or stress on aheart muscle fiber as it contracts is termed the afterload. Becausepressure within the ventricles rises rapidly from a diastolic to asystolic value as blood is pumped out into the aorta and pulmonaryarteries, the part of the ventricle that first contracts due to anexcitatory stimulation pulse does so against a lower afterload than doesa part of the ventricle contracting later. Thus a myocardial regionwhich contracts later than other regions is subjected to both anincreased preload and afterload. This situation is created frequently bythe ventricular conduction delays associated with heart failure andventricular dysfunction due to an MI. The increased wall stress to thelate-activating myocardial regions is most probably the trigger forventricular remodeling. By pacing one or more sites in a ventricle nearthe infarcted region in a manner which may cause a more coordinatedcontraction, CRT provides pre-excitation of myocardial regions whichwould otherwise be activated later during systole and experienceincreased wall stress. The pre-excitation of the remodeled regionrelative to other regions unloads the region from mechanical stress andallows reversal or prevention of remodeling to occur.

Cardioversion, an electrical shock delivered to the heart synchronouslywith the QRS complex, and defibrillation, an electrical shock deliveredwithout synchronization to the QRS complex, can be used to terminatemost tachyarrhythmias. The electric shock terminates the tachyarrhythmiaby simultaneously depolarizing the myocardium and rendering itrefractory. A class of CRM devices known as an implantable cardioverterdefibrillator (ICD) provides this kind of therapy by delivering a shockpulse to the heart when the device detects tachyarrhythmias. Anothertype of electrical therapy for tachycardia is anti-tachycardia pacing(ATP). In ventricular ATP, the ventricles are competitively paced withone or more pacing pulses in an effort to interrupt the reentrantcircuit causing the tachycardia. Modern ICDs typically have ATPcapability, and deliver ATP therapy or a shock pulse when atachyarrhythmia is detected.

Devices/Systems/Methods

FIG. 1 illustrates a neural stimulator device embodiment. Theillustrated device 100 is adapted to deliver chronic neural stimulation.The device can be designed as an implantable device or an externaldevice. A device embodiment includes an implantable device that provideschronic vagus nerve stimulation. The illustrated device includes anon-selective vagus nerve stimulation therapy delivery system 101adapted to deliver a neural stimulation signal to the neural stimulationelectrode(s) or transducer(s) 102 to deliver the neural stimulationtherapy. Examples of neural stimulation electrodes include nerve cuffelectrodes, intravascularly placed electrodes, and transcutaneouselectrodes. Examples of neural stimulation transducers includesultrasound, light and magnetic energy transducers. A controller 103appropriately controls the neural stimulation therapy delivery system101 to provide the appropriate neural stimulation signal to theelectrode(s)/transducer(s) that results in a desired neural stimulationtherapy. The illustrated device includes a memory 104 to storeprogrammable parameters 105. The controller 103 implements a neuralstimulation therapy using the programmable parameters. Examples ofprogrammable parameters 105, any one or more of which can be stored inthe memory, include a therapy duration parameter, a therapy period, aswell as a duty cycle, and a stimulation therapy for intermittentstimulation. The programmable parameters can also include parametersused to adjust the intensity of the neural stimulation therapy, such asamplitude, frequency, pulse width, and stimulation schedule parameters.The illustrated device 100 includes a transceiver 106 adapted tocommunicate with an external device (e.g. programmer) for use inreceiving programming instructions. The illustrated device 100 includesat least one port 107 for receiving neural stimulation therapy inputs orneural stimulation feedback inputs (including both therapy and feedbackinputs according to some embodiments). The input can receive acommunication from a device programmer, for use by a physician orpatient in changing the programmable parameters based on observedconditions. The input can receive a feedback from physiologic sensorsused to monitor physiologic responses to the neural stimulation.Examples of such sensors used to provide feedback for the transitionprotocol include heart rate and blood pressure sensors.

The illustrated device 100 includes a clock/timer 108, used by thecontroller 103 to control timing of the neural stimulation signals forthe neural stimulation therapy. The illustrated controller 103 includesa neural stimulation scheduler 109, which uses the clock/timer andschedule parameter(s) to control the stimulation delivered by thedelivery system 101. The scheduler uses at least one schedule parameterselected to avoid physiological habituation to the neural stimulationtherapy. Some scheduler embodiments use a duration parameter(s) 110 tocontrol the therapy duration per therapy period, and some schedulerembodiments use a therapy period parameter 111 to control a duration oftime before a subsequent therapy is applied. For example, someembodiments use a therapy period of approximately one day, and use atherapy duration of approximately 8 hours each day. These parameter(s)can represent limits (e.g. maximum, minimum, range) for the parametervalues. Some embodiments, for example, use the therapy durationparameter as a minimum value, such that at least that duration of thetherapy will be applied per therapy period (e.g. at least 8 hours oftherapy per day). The delivered therapy can be intermittent orcontinuous. Some scheduler embodiments use parameter(s) to controlintermittent stimulation during the therapy period, such as duty cycle112 or stimulation period 113. The duty cycle represents the percentageof time during which stimulation is delivered for a stimulation period.A therapy period (e.g. on the order of a day) can include manystimulation periods (e.g. less than five minutes or on the order of oneminute). Some embodiments limit the duty cycle to less thanapproximately 50%, some embodiments limit the duty cycle to less thanapproximately 25%, and some embodiments limit the duty cycle to a rangebetween 10% and 20%. A scheduler embodiment implements a protocol whereneural stimulation is delivered for approximately ten seconds everyminute (e.g. duty cycle of approximately 17% and a stimulation period ofapproximately one minute). The scheduler parameters can include startand stop parameters, start and duration parameters, or other parametersthat can be used to control the schedule of neural stimulation. Some ofthe parameter examples can be derived from others (e.g. start and stoptimes can be derived from start and duration). Some embodiments of thescheduler program or limit the stimulation period, where a train ofneural stimulation pulses occurs with each stimulation period. Forexample, some embodiments limit or program the stimulation period to avalue less than five minutes, and some embodiments limit or program thestimulation period to a value on the order of one minute (e.g. 50seconds).

The illustrated controller 103 also includes a module to control neuralstimulation intensity 114. Therapy inputs and/or therapy feedback 107can be used to appropriately adjust one or more stimulation parameter(s)to increase, decrease or maintain a desired neural stimulationintensity. For example, the amplitude, frequency, and/or pulse width ofa neural stimulation pulse train can be adjusted to titrate the neuralstimulation intensity. Some embodiments adjust the neural stimulationschedule to adjust the neural stimulation intensity. Examples ofschedule parameters include therapy duration, start/stop times,stimulation period, stimulation train duration per stimulation period,and duty cycle. For embodiments that allow some schedule parameters tobe modified, as illustrated by the line between the neural stimulationschedule in the neural stimulation intensity module 114 and the neuralstimulation scheduler 109, the scheduler limits the extent of anyallowed modifications to the schedule parameters. For example, the dutycycle of the stimulation can be adjusted to a value less than or equalto the maximum duty cycle (e.g. 50%) permitted by the scheduler orwithin a range of duty cycles permitted by the scheduler. In anotherexample, the therapy duration can be adjusted to a value greater than orequal to the minimum value (e.g. 8 hours per day) for the duration ofthe therapy permitted by the controller.

Advanced patient management systems can be used to enable the patientand/or doctor to adjust parameter(s) to avoid observed or sensedhabituation, or to adjust therapy intensity. The inputs can be providedby computers, programmers, cell phones, personal digital assistants, andthe like. The patient can call a call center using a regular telephone,a mobile phone, or the internet. The communication can be through arepeater, similar to that used in Boston Scientific's Latitude patientmanagement system. In response, the call center (e.g. server in callcenter) can automatically send information to the device to adjust ortitrate the therapy. The call center can inform the patient's physicianof the event. A device interrogation can be automatically triggered. Theresults of the device interrogation can be used to determine if and howthe therapy should be adjusted and/or titrated to improve the transientresponse. A server can automatically adjust and/or titrate the therapyusing the results of the device interrogation. Medical staff can reviewthe results of the device interrogation, and program the device throughthe remote server to provide the desired therapy adjustments and/ortitrations. The server can communicate results of the deviceinterrogation to the patient's physician, who can provide input ordirection for adjusting and/or titrating the therapy.

Various embodiments of the present subject matter relate to neuralstimulation therapy (NST) that includes intermittent neural stimulation.Some of the terms used to discuss intermittent stimulation areillustrated in FIGS. 2 and 3. Intermittent neural stimulation can bedelivered using a duty cycle of a stimulation period. FIGS. 2 and 3 plotneural stimulation intensity against time. FIG. 2 illustrates variablestimulation periods (SP) and duty cycles (DC), and FIG. 3 illustratesconstant stimulation periods (SP) and duty cycles (DC). Each duty cyclecan include a train of neural stimulation pulses. The duty cycle andstimulation period need not be constant throughout the NST. For example,the duration or frequency of the duty cycle can be adjusted to adjust anintensity of the NST. Also, the start and/or stop of the duty cycle canbe dependent on enabling conditions. The duty cycle and/or stimulationperiod can be adjusted in every subsequent stimulation period. Unlessexpressly disclosed otherwise herein, “stimulation period” and “dutycycle” are not intended to only encompass constant values that result inneural stimulation in a precise periodic manner (e.g. FIG. 3), butrather is intended to include intermittent neural stimulation wheretherapeutically-effective or prophylactically-effective neuralstimulation is delivered for a time and then not delivered for a time,and then delivered for a time (e.g. FIG. 2).

The neural stimulation delivered during the duty cycle can be deliveredusing a variety of neural stimulation techniques, such as stimulationthat uses electrical, ultrasound, thermal, magnetic, light or mechanicalenergy. Electrical neural stimulation is used in this document as anexample of neural stimulation. In electrical stimulation, for example, atrain of neural stimulation pulses (current or voltage) can be deliveredduring a duty cycle of stimulation. Stimulation waveforms can be squarepulses or other morphologies. The stimulation pulses can be monophasicor biphasic pulses.

In addition to controlling the schedule of the neural stimulation toavoid physiological habituation to the stimulation, some embodimentsalso implement a protocol designed to mimic the effects of thenaturally-occurring pulse pressure, as provided in U.S. application Ser.No. 10/962,845, filed Oct. 12, 2004 (U.S. Published Application2006/0079945). As discussed therein, the baroreflex adapts to increasedbaroreflex stimulation. Static or constant baroreflex stimulation causesa quick or immediate response which gradually diminishes. Over time, thebaroreflex resets and returns to the baseline response, which rendersstatic stimulation ineffective. Thus, baroreflex adaptation poses aproblem for sustaining baroreflex therapy that effectively inhibits SNA.

FIG. 4 illustrates baroreflex adaptation using a relationship betweencarotid sinus pressure 415, sympathetic nerve activity (SNA) 416 andmean arterial pressure (MAP) 417. Internal pressure and stretching ofthe arterial wall, such as that which occurs at the carotid sinus,naturally activates the baroreflex and the baroreflex inhibits SNA. Thecarotid sinus pressure, the SNA and the MAP are illustrated for thefollowing four time segments: (1) relatively low and constant carotidsinus pressure indicated at 418; (2) relatively high and constantcarotid sinus pressure indicated at 419; (3) relatively high and pulsedcarotid sinus pressure indicated at 420; and (4) a return to arelatively high and constant carotid sinus pressure indicated at 421.

When the carotid sinus pressure is relatively low and constant, asillustrated at 418, the SNA is relatively high and constant, and thepulsating MAP is relatively high. When the carotid sinus pressure isincreased to a relatively high and constant pressure at transition 422,the SNA and MAP initially decrease due to the baroreflex and thenincreases due to the quick adaptation of the baroreflex to the increasedcarotid sinus pressure. However, when the carotid sinus pressurepulsates similar to naturally-occurring blood pressure pulses, asillustrated at 420, the SNA and MAP decrease to relatively low levelsand are maintained at these relatively low levels. When the carotidsinus pressure changes from a pulsed to constant pressure at transition423, the SNA and MAP both increase again due to the adaptation of thebaroreflex. Some embodiments modulate the baroreflex stimulation tomimic the effects of the naturally-occurring pulse pressure and preventbaroreflex adaptation.

FIG. 5 illustrates a method to periodically modulate neural stimulation,according to various embodiments of the present subject matter. At 524,it is determined whether neural stimulation is to be provided. Upondetermining that neural stimulation is to be provided, neuralstimulation is applied with periodic modulation to mimic pulsatilepressure, as generally illustrated at 525. In various embodiments, theperiodic modulation, or other variation, of the neural stimulationsignal is based on detected pulsatile information 526 such as a detectedpulse rate 527 and/or a detected pulse phase 528. Some embodimentsfurther base the periodic modulation based on detected feedbackparameters 529, such as detected respiration, detected nerve traffic,detected blood pressure, and the like. These feedback parameters allowthe stimulation to be tailored to achieve a desired effect.

An embodiment of the neural stimulation therapy delivery system 101illustrated in FIG. 1 uses neural stimulation waveforms disclosed inU.S. application Ser. No. 11/468,135, filed Aug. 29, 2006.According toan embodiment, the stimulation circuitry is configured to deliver awaveform for neural stimulation with the following approximateparameters: frequency=20 Hz; pulse width=300 microseconds;amplitude=1.5-2.0 mA. This waveform can be delivered as a pulse trainapplied either continuously or intermittently (e.g., with a dutycycle=10 sec ON, 50 sec OFF) in order to provide, for example,anti-remodeling therapy to post-MI or heart failure patients. Suchstimulation may be applied either chronically or periodically inaccordance with lapsed time intervals or sensed physiologicalconditions. This waveform has been demonstrated in pre-clinical studiesto be a particularly effective anti-remodeling therapy when applied tothe vagus nerve in the cervical region, where the stimulation may beapplied through either a nerve cuff or a transvascular lead. Thestimulating configuration for delivering the waveform may be any of theconfigurations described in this document such as either a bipolarconfiguration or a unipolar configuration with a far-field subcutaneousreturn electrode. The stimulation circuitry may be either dedicated todelivering neural stimulation or may be configured to also deliverwaveforms suitable for CRM.

A neural stimulation waveform may be delivered with phases ofalternating polarity, referred to herein as first and second phases. Forexample, the waveform may be delivered as monophasic pulses with abipolar stimulating configuration and with a “bipolar switch” so thatthe phase of the monophasic pulses is alternated in each consecutivepulse train. That is, a pulse train with monophasic pulses having firstphases of one polarity is then followed by a pulse train with monophasicpulses having second phases of the opposite polarity. FIGS. 6 and 7 showexample waveforms as would be produced by recording the potentialbetween the stimulation electrodes. FIG. 6 shows an example of such awaveform in which a monophasic pulse train MPT1 having first phases FP1of positive polarity is followed by a monophasic pulse train MPT2 havingsecond phases SP1 of negative polarity. In another embodiment, thestimulation circuitry may be configured to deliver a pulse train withbiphasic pulses so that the first phase alternates with the second phase(i.e., each consecutive pulse in the train alternates in polarity). FIG.7 shows an example of a biphasic pulse train BPT1 having first phasesFP2 and second phases SP2 that alternate in polarity. Such biphasicpulse trains with alternating polarities or a series of monophasicpulses trains having alternating polarities may be applied continuouslyor on a periodic or intermittent basis for a specified period of time.

FIGS. 8 and 9 show example waveforms as would be produced by acapacitive discharge pulse output circuit, which correspond to thewaveforms of FIGS. 6 and 7, respectively. With a capacitive dischargepulse output circuit, the voltage amplitude of each pulse is notconstant as is the case with a current source pulse output circuit.FIGS. 8 and 9 thus show pulses in which the voltage rises to an initialvalue and then decays as the output capacitor discharges. Also, thecircuitry may incorporate a passive recharge between monophasic pulsesin order to dissipate afterpotentials from the stimulation electrodes.FIG. 8 shows such passive recharge cycles where the output circuitry isswitched in a manner that causes the voltage between pulses overshootsslightly in a direction opposite to the pulses and decays to zero as theafterpotentials between the stimulation electrodes discharge. Passiverecharge is not needed in the case of biphasic pulses as each pulsedischarges the afterpotential produced by the preceding pulse. FIG. 9shows an interphase delay IPD between biphasic pulses. In certainembodiments, it may be desirable to minimize or even eliminate thisdelay.

FIGS. 10 and 11 illustrate embodiments of circuitry for deliveringstimulation pulse trains as described above. In FIG. 10, a currentsource pulse output circuit 1030 outputs current pulses betweenstimulation electrodes 1031A and 1031B in accordance with command inputsfrom the controller 1032. The command inputs from the controller specifythe timing of the pulses, pulse widths, current amplitude, and polarity.FIG. 11 illustrates an embodiment in which a capacitive discharge pulseoutput circuit 1133 is used to output voltage pulses between stimulationelectrodes 1134A and 1134B in accordance with command inputs from thecontroller 1135. In this embodiment, the command inputs from thecontroller specify the timing of the pulses, pulse widths, voltageamplitude, and pulse polarity. In order for the controller to specify avoltage amplitude that results in a desired current amplitude for thepulses, the lead impedance may be measured by lead impedance measurementcircuit 1136. The output capacitor of the pulse output circuit may thenbe charged to the appropriate voltage for each pulse. In order tomonitor the lead impedance, the controller is programmed toperiodically, or upon command from a user via telemetry, charge theoutput capacitor to a known voltage level, connect the output capacitorto the stimulation leads to deliver a stimulation pulse, and measure thetime it takes for the capacitor voltage to decay by a certain amount(e.g., to half of the initial value). In order to minimize patientdiscomfort, the lead impedance procedure should be performed using aslow a voltage as possible. In one embodiment, the controller isprogrammed to use a first voltage amplitude (e.g., 1 volt) and thencompare the measurement count (i.e., the capacitor decay time) to aspecified minimum value CntZMin. If the measurement count is belowCntZMin, the current delivered during the test is deemed too small forthe measurement to be accurate. A second measurement pulse is thendelivered at a higher second voltage (e.g., 2 volts). If that count isagain below CntZMin, a third measurement pulse is delivered at a stillhigher third voltage (e.g., 4 volts). With a typical stimulation lead,this procedure limits the measurement current to between roughly 1 mAand 0.6 mA.

In an embodiment, with either a biphasic pulse train or a series ofmonophasic pulse trains having alternating polarities, the stimulationparameters for the first and second phases may be adjusted separately.For example, the pulse widths and amplitudes for the first and secondphases of a biphasic pulse train may be selected to be the same ordifferent. In the case of a series of monophasic pulse trains havingalternating polarities, the pulse width, pulse amplitude, duty cycle,and frequency for each of the first and second phases may be selected tobe the same or different.

In an embodiment, advantage is taken of an empirical finding thatstimulation of the vagus nerve with pulses of different polarities canhave different effects. It has been found that vagal stimulation withalternating polarities, delivered as either a biphasic pulse train or bymonophasic pulse trains with alternating polarities, results not only inthe desired therapeutic effect for preventing or reversing cardiacremodeling as described above, but also with a reduction of undesiredside effects. Such side effects from vagal stimulation may include, forexample, hoarseness and coughing due to vagal innervation of the larynx.In order to achieve an optimum balance between therapeutic effects andundesired side effects, a neural stimulation waveform with alternatingpolarities may be applied over time while varying the pulse amplitudesand pulse widths for each polarity. As the pulse amplitudes and widthsare varied, a clinical determination may be made as to the therapeuticbenefit provided and the extent of any undesired side effects. Forexample, a biphasic pulse train or a series monophasic pulse trains withalternating polarities may be applied in which the pulse amplitude andpulse width for one polarity are titrated to a therapeutic dose. Thepulse amplitude and pulse width for the opposite polarity are thenadjusted to control the presence of side-effects. Which one of the twopolarities of the pulse train is responsible for producing therapeuticbenefits and which polarity is responsible for reducing side effects maybe determined empirically. Such a titration procedure may be performedby a clinician after implantation of the device, where the stimulationparameters such as pulse width and amplitude are adjusted via telemetry.The device could also be configured to automatically titrate thetherapeutic dose to a target amplitude within a specified period oftime. For example, such a titration could be performed rapidly duringthe first 1-2 weeks after an MI, which has been shown in pre-clinicalstudies to be the time where the greatest therapeutic benefit isachieved.

The pulse frequency, pulse width, pulse amplitude, pulse polarity, andbipolar/unipolar stimulation configuration can be programmableparameters, the optimal settings of which depend upon the stimulationsite and type of stimulation electrode. The device may also be equippedwith different sensing modalities for sensing physiological variablesaffected by neural stimulation. The device may then be programmed to usethese variables in controlling the delivery of neural stimulation.

FIG. 12 illustrates a system 1237 including an implantable medicaldevice (IMD) 1238 and an external system or device 1239, according tovarious embodiments of the present subject matter. Various embodimentsof the IMD include NS functions or include a combination of NS and CRMfunctions. The IMD may also deliver biological agents and pharmaceuticalagents. The external system and the IMD are capable of wirelesslycommunicating data and instructions. In various embodiments, forexample, the external system and IMD use telemetry coils to wirelesslycommunicate data and instructions. Thus, the programmer can be used toadjust the programmed therapy provided by the IMD, and the IMD canreport device data (such as battery and lead resistance) and therapydata (such as sense and stimulation data) to the programmer using radiotelemetry, for example. According to various embodiments, the IMDstimulates/inhibits a neural target using non-selective vagus nervestimulation delivered using a predetermined schedule and with scheduleparameter(s) selected to avoid physiological habituation to the vagusnerve stimulation.

The external system allows a user such as a physician or other caregiveror a patient to control the operation of the IMD and obtain informationacquired by the IMD. In one embodiment, external system includes aprogrammer communicating with the IMD bi-directionally via a telemetrylink. In another embodiment, the external system is a patient managementsystem including an external device communicating with a remote devicethrough a telecommunication network. The external device is within thevicinity of the IMD and communicates with the IMD bi-directionally via atelemetry link. The remote device allows the user to monitor and treat apatient from a distant location. The patient monitoring system isfurther discussed below.

The telemetry link provides for data transmission from implantablemedical device to external system. This includes, for example,transmitting real-time physiological data acquired by IMD, extractingphysiological data acquired by and stored in IMD, extracting therapyhistory data stored in implantable medical device, and extracting dataindicating an operational status of the IMD (e.g., battery status andlead impedance). Telemetry link also provides for data transmission fromexternal system to IMD. This includes, for example, programming the IMDto acquire physiological data, programming IMD to perform at least oneself-diagnostic test (such as for a device operational status), andprogramming the IMD to deliver at least one therapy.

FIG. 13 illustrates a system 1340 including an external device 1341, animplantable neural stimulator (NS) device 1342 and an implantablecardiac rhythm management (CRM) device 1343, according to variousembodiments of the present subject matter. Various aspects involve amethod for communicating between an NS device and a CRM device or othercardiac stimulator. In various embodiments, this communication allowsone of the devices 1342 or 1343 to deliver more appropriate therapy(i.e. more appropriate NS therapy or CRM therapy) based on data receivedfrom the other device. Some embodiments provide on-demandcommunications. In various embodiments, this communication allows eachof the devices to deliver more appropriate therapy (i.e. moreappropriate NS therapy and CRM therapy) based on data received from theother device. The illustrated NS device and the CRM device are capableof wirelessly communicating with each other, and the external system iscapable of wirelessly communicating with at least one of the NS and theCRM devices. For example, various embodiments use telemetry coils towirelessly communicate data and instructions to each other. In otherembodiments, communication of data and/or energy is by ultrasonic means.Rather than providing wireless communication between the NS and CRMdevices, various embodiments provide a communication cable or wire, suchas an intravenously-fed lead, for use to communicate between the NSdevice and the CRM device. In some embodiments, the external systemfunctions as a communication bridge between the NS and CRM devices.

FIGS. 14-15 and 18-19 illustrate system embodiments adapted to providevagal stimulation, and are illustrated as bilateral systems that canstimulate both the left and right vagus nerve. Those of ordinary skillin the art will understand, upon reading and comprehending thisdisclosure, that systems can be designed to stimulate only the rightvagus nerve, systems can be designed to stimulate only the left vagusnerve, and systems can be designed to bilaterally stimulate both theright and left vagus nerves. The systems can be designed to stimulatenerve traffic (providing a parasympathetic response when the vagus isstimulated), or to inhibit nerve traffic (providing a sympatheticresponse when the vagus is inhibited). Various embodiments deliverunidirectional stimulation or selective stimulation of some of the nervefibers in the nerve.

FIG. 14 illustrates a system embodiment in which an implantable medicaldevice (IMD) 1444 is placed subcutaneously or submuscularly in apatient's chest with lead(s) 1445 positioned to stimulate a vagus nerve.According to various embodiments, neural stimulation lead(s) 1445 aresubcutaneously tunneled to a neural target, and can have a nerve cuffelectrode to stimulate the neural target. Some vagus nerve stimulationlead embodiments are intravascularly fed into a vessel proximate to theneural target, and use electrode(s) within the vessel to transvascularlystimulate the neural target. For example, some embodiments stimulate thevagus using electrode(s) positioned within the internal jugular vein.Other embodiments deliver neural stimulation to the neural target fromwithin the trachea, the laryngeal branches of the internal jugular vein,and the subclavian vein. The neural targets can be stimulated usingother energy waveforms, such as ultrasound and light energy waveforms.Other neural targets can be stimulated, such as cardiac nerves andcardiac fat pads. The illustrated system includes leadless ECGelectrodes 1446 on the housing of the device. These ECG electrodes arecapable of being used to detect heart rate, for example. Heart rate canbe used as a feedback to titrate the neural stimulation intensity.However, the neural stimulation is delivered based upon a predeterminedschedule with schedule parameter(s) selected to avoid physiologicalhabituation to the vagus nerve stimulation, and is not initiatedon-demand based on the heart rate.

FIG. 15 illustrates a system embodiment that includes an implantablemedical device (IMD) 1544 with satellite electrode(s) 1545 positioned tostimulate at least one neural target. The satellite electrode(s) areconnected to the IMD, which functions as the planet for the satellites,via a wireless link. Stimulation and communication can be performedthrough the wireless link. Examples of wireless links include RF linksand ultrasound links. Examples of satellite electrodes includesubcutaneous electrodes, nerve cuff electrodes and intravascularelectrodes. Various embodiments include satellite neural stimulationtransducers used to generate neural stimulation waveforms such asultrasound and light waveforms. The illustrated system includes leadlessECG electrodes 1546 on the housing of the device. These ECG electrodesare capable of being used to detect heart rate, for example. Heart ratecan be used as a feedback to titrate the neural stimulation intensity.However, the neural stimulation is delivered based upon a predeterminedschedule with schedule parameter(s) selected to avoid physiologicalhabituation to the vagus nerve stimulation, and is not initiatedon-demand based on the heart rate.

FIG. 16 illustrates an implantable medical device (IMD) 1647 having aneural stimulation (NS) component 1648 and a cardiac rhythm management(CRM) component 1649 according to various embodiments of the presentsubject matter. The illustrated device includes a controller 1650 andmemory 1651. According to various embodiments, the controller includeshardware, software, or a combination of hardware and software to performthe neural stimulation and CRM functions. For example, the programmedtherapy applications discussed in this disclosure are capable of beingstored as computer-readable instructions embodied in memory and executedby one or more processors. For example, therapy schedule(s) andprogrammable parameters can be stored in memory. According to variousembodiments, the controller includes a processor to execute instructionsembedded in memory to perform the neural stimulation and CRM functions.The illustrated neural stimulation therapy 1652 can include any neuralstimulation therapy, such as a vagus nerve stimulation therapy for heartfailure. Various embodiments include CRM therapies 1653, such asbradycardia pacing, anti-tachycardia therapies such as ATP,defibrillation and cardioversion, and cardiac resynchronization therapy(CRT). The illustrated device further includes a transceiver 1654 andassociated circuitry for use to communicate with a programmer or anotherexternal or internal device. Various embodiments include a telemetrycoil.

The CRM therapy section 1649 includes components, under the control ofthe controller, to stimulate a heart and/or sense cardiac signals usingone or more electrodes. The illustrated CRM therapy section includes apulse generator 1655 for use to provide an electrical signal through anelectrode to stimulate a heart, and further includes sense circuitry1656 to detect and process sensed cardiac signals. An interface 1657 isgenerally illustrated for use to communicate between the controller 1650and the pulse generator 1655 and sense circuitry 1656. Three electrodesare illustrated as an example for use to provide CRM therapy. However,the present subject matter is not limited to a particular number ofelectrode sites. Each electrode may include its own pulse generator andsense circuitry. However, the present subject matter is not so limited.The pulse generating and sensing functions can be multiplexed tofunction with multiple electrodes.

The NS therapy section 1648 includes components, under the control ofthe controller, to stimulate a neural stimulation target and/or senseparameters associated with nerve activity or surrogates of nerveactivity such as blood pressure and respiration. Three interfaces 1658are illustrated for use to provide neural stimulation. However, thepresent subject matter is not limited to a particular number interfaces,or to any particular stimulating or sensing functions. Pulse generators1659 are used to provide electrical pulses to transducer or transducersfor use to stimulate a neural stimulation target. According to variousembodiments, the pulse generator includes circuitry to set, and in someembodiments change, the amplitude of the stimulation pulse, the pulsewidth of the stimulation pulse, the frequency of the stimulation pulse,the burst frequency of the pulse, and the morphology of the pulse suchas a square wave, triangle wave, sinusoidal wave, and waves with desiredharmonic components to mimic white noise or other signals. Sensecircuits 1660 are used to detect and process signals from a sensor, suchas a sensor of nerve activity, blood pressure, respiration, and thelike. The interfaces 1658 are generally illustrated for use tocommunicate between the controller 1650 and the pulse generator 1659 andsense circuitry 1660. Each interface, for example, may be used tocontrol a separate lead. Various embodiments of the NS therapy sectiononly includes a pulse generator to stimulate a neural target. Theillustrated device further includes a clock/timer 1661, which can beused to deliver the programmed therapy according to a programmedstimulation protocol and/or schedule.

FIG. 17 shows a system diagram of an embodiment of amicroprocessor-based implantable device, according to variousembodiments. The controller of the device is a microprocessor 1762 whichcommunicates with a memory 1763 via a bidirectional data bus. Thecontroller could be implemented by other types of logic circuitry (e.g.,discrete components or programmable logic arrays) using a state machinetype of design. As used herein, the term “circuitry” should be taken torefer to either discrete logic circuitry or to the programming of amicroprocessor. Shown in the figure are three examples of sensing andpacing channels designated “A” through “C” comprising bipolar leads withring electrodes 1764A-C and tip electrodes 1765A-C, sensing amplifiers1766A-C, pulse generators 1767A-C, and channel interfaces 1768A-C. Eachchannel thus includes a pacing channel made up of the pulse generatorconnected to the electrode and a sensing channel made up of the senseamplifier connected to the electrode. The channel interfaces 1768A-Ccommunicate bidirectionally with the microprocessor 1762, and eachinterface may include analog-to-digital converters for digitizingsensing signal inputs from the sensing amplifiers and registers that canbe written to by the microprocessor in order to output pacing pulses,change the pacing pulse amplitude, and adjust the gain and thresholdvalues for the sensing amplifiers. The sensing circuitry of thepacemaker detects a chamber sense, either an atrial sense or ventricularsense, when an electrogram signal (i.e., a voltage sensed by anelectrode representing cardiac electrical activity) generated by aparticular channel exceeds a specified detection threshold. Pacingalgorithms used in particular pacing modes employ such senses to triggeror inhibit pacing. The intrinsic atrial and/or ventricular rates can bemeasured by measuring the time intervals between atrial and ventricularsenses, respectively, and used to detect atrial and ventriculartachyarrhythmias.

The electrodes of each bipolar lead are connected via conductors withinthe lead to a switching network 1769 controlled by the microprocessor.The switching network is used to switch the electrodes to the input of asense amplifier in order to detect intrinsic cardiac activity and to theoutput of a pulse generator in order to deliver a pacing pulse. Theswitching network also enables the device to sense or pace either in abipolar mode using both the ring and tip electrodes of a lead or in aunipolar mode using only one of the electrodes of the lead with thedevice housing (can) 1770 or an electrode on another lead serving as aground electrode. A shock pulse generator 1771 is also interfaced to thecontroller for delivering a defibrillation shock via shock electrodes1772 and 1773 to the atria or ventricles upon detection of a shockabletachyarrhythmia.

Neural stimulation channels, identified as channels D and E, areincorporated into the device for delivering parasympathetic stimulationand/or sympathetic inhibition, where one channel includes a bipolar leadwith a first electrode 1774D and a second electrode 1775D, a pulsegenerator 1776D, and a channel interface 1777D, and the other channelincludes a bipolar lead with a first electrode 1774E and a secondelectrode 1775E, a pulse generator 1776E, and a channel interface 1777E.Other embodiments may use unipolar leads in which case the neuralstimulation pulses are referenced to the can or another electrode. Otherembodiments may use tripolar or multipolar leads. In variousembodiments, the pulse generator for each channel outputs a train ofneural stimulation pulses which may be varied by the controller as toamplitude, frequency, duty-cycle, and the like. In this embodiment, eachof the neural stimulation channels uses a lead which can beintravascularly disposed near an appropriate neural target. Other typesof leads and/or electrodes may also be employed. A nerve cuff electrodemay be used in place of an intravascularly disposed electrode to provideneural stimulation. In some embodiments, the leads of the neuralstimulation electrodes are replaced by wireless links.

The figure illustrates a telemetry interface 1778 connected to themicroprocessor, which can be used to communicate with an externaldevice. The illustrated microprocessor 1762 is capable of performingneural stimulation therapy routines and myocardial (CRM) stimulationroutines. Examples of NS therapy routines include a vagus nervestimulation therapies to treat ventricular remodeling, hypertension, andheart failure. The present subject matter is not limited to a particularneural stimulation therapy. Examples of myocardial therapy routinesinclude bradycardia pacing therapies, anti-tachycardia shock therapiessuch as cardioversion or defibrillation therapies, anti-tachycardiapacing therapies (ATP), and cardiac resynchronization therapies (CRT).

FIG. 18 illustrates an IMD 1844 placed subcutaneously or submuscularlyin a patient's chest with lead(s) 1879 positioned to provide a CRMtherapy to a heart, and with lead(s) 1845 positioned to stimulate and/orinhibit neural traffic at a neural target, such as a vagus nerve,according to various embodiments. According to various embodiments,neural stimulation lead(s) are subcutaneously tunneled to a neuraltarget, and can have a nerve cuff electrode to stimulate the neuraltarget. Some lead embodiments are intravascularly fed into a vesselproximate to the neural target, and use transducer(s) within the vesselto transvascularly stimulate the neural target. For example, someembodiments target the vagus nerve using electrode(s) positioned withinthe internal jugular vein.

FIG. 19 illustrates an IMD 1944 with lead(s) 1979 positioned to providea CRM therapy to a heart, and with satellite transducers 1945 positionedto stimulate/inhibit a neural target such as a vagus nerve, according tovarious embodiments. The satellite transducers are connected to the IMD,which functions as the planet for the satellites, via a wireless link.Stimulation and communication can be performed through the wirelesslink. Examples of wireless links include RF links and ultrasound links.Although not illustrated, some embodiments perform myocardialstimulation using wireless links. Examples of satellite transducersinclude subcutaneous electrodes, nerve cuff electrodes and intravascularelectrodes.

FIG. 20 is a block diagram illustrating an embodiment of an externalsystem 2080. The external system includes a programmer, in someembodiments. In the illustrated embodiment, the external system includesa patient management system. As illustrated, the external system 2080 isa patient management system including an external device 2082, atelecommunication network 2083, and a remote device 2084. The externaldevice 2080 is placed within the vicinity of an implantable medicaldevice (IMD) and includes an external telemetry system 2085 tocommunicate with the IMD. The remote device(s) 2084 is in one or moreremote locations and communicates with the external device 2082 throughthe network 2083, thus allowing a physician or other caregiver tomonitor and treat a patient from a distant location and/or allowingaccess to various treatment resources from the one or more remotelocations. The illustrated remote device 2084 includes a user interface2086. According to various embodiments, the external device 2082includes a neural stimulator, a programmer or other device such as acomputer, a personal data assistant or phone. The external device 2082,in various embodiments, includes two devices adapted to communicate witheach other over an appropriate communication channel, such as a computerby way of example and not limitation. The external device can be used bythe patient or physician to provide side effect feedback indicative ofpatient discomfort, for example.

According to various embodiments, the device, as illustrated anddescribed above, is adapted to deliver neural stimulation as electricalstimulation to desired neural targets, such as through one or morestimulation electrodes positioned at predetermined location(s). Otherelements for delivering neural stimulation can be used. For example,some embodiments use transducers to deliver neural stimulation usingother types of energy, such as ultrasound, light, magnetic or thermalenergy.

One of ordinary skill in the art will understand that, the modules andother circuitry shown and described herein can be implemented usingsoftware, hardware, and combinations of software and hardware. As such,the terms module and circuitry, for example, are intended to encompasssoftware implementations, hardware implementations, and software andhardware implementations.

The methods illustrated in this disclosure are not intended to beexclusive of other methods within the scope of the present subjectmatter. Those of ordinary skill in the art will understand, upon readingand comprehending this disclosure, other methods within the scope of thepresent subject matter. The above-identified embodiments, and portionsof the illustrated embodiments, are not necessarily mutually exclusive.These embodiments, or portions thereof, can be combined. In variousembodiments, the methods are implemented using a computer data signalembodied in a carrier wave or propagated signal, that represents asequence of instructions which, when executed by one or more processorscause the processor(s) to perform the respective method. In variousembodiments, the methods are implemented as a set of instructionscontained on a computer-accessible medium capable of directing aprocessor to perform the respective method. In various embodiments, themedium is a magnetic medium, an electronic medium, or an optical medium.

The above detailed description is intended to be illustrative, and notrestrictive. Other embodiments will be apparent to those of skill in theart upon reading and understanding the above description. The scope ofthe invention should, therefore, be determined with reference to theappended claims, along with the full scope of equivalents to which suchclaims are entitled.

1. A method for delivering a vagal stimulation therapy to a vagus nerve,comprising: stimulating the vagus nerve, wherein stimulating the vagusnerve includes simultaneously stimulating both afferent axons andefferent axons in the vagus nerve; and avoiding physiologicalhabituation to stimulating the vagus nerve, wherein avoidingphysiological habituation includes scheduling stimulation of the vagusnerve to provide a stimulation schedule using a programmable value for atherapy duration to control a therapy period or a programmable value foran intermittent neural stimulation parameter associated with on/offtiming for stimulating the vagus nerve, wherein stimulating the vagusnerve includes stimulating the vagus nerve according to the stimulationschedule.
 2. The method of claim 1, wherein stimulating the vagus nerveaccording to the stimulation schedule includes stimulating the vagusnerve independent of sensed heart rate.
 3. The method of claim 1,wherein avoiding physiological habituation includes accounting for eachneural stimulation train in the therapy period to provide an indicatorfor total therapy time using the value for the therapy duration as aminimum therapy duration for the therapy period.
 4. The method of claim3, the method further comprising delivering intermittent therapy duringthe therapy duration.
 5. The method of claim 3, the method furthercomprising delivering continuous therapy during the therapy duration. 6.The method of claim 1, wherein avoiding physiological habituationincludes: controlling a duty cycle for stimulating the vagus nerve usingthe programmable value for the intermittent neural stimulationparameter; and limiting a stimulation period during which the neuralstimulation signal is delivered, wherein the duty cycle corresponds to apercentage of the stimulation period.
 7. The method of claim 6, whereinthe stimulation period is approximately one minute, and delivering theneural stimulation signal includes, for every stimulation period,delivering the neural stimulation signal for approximately ten secondsof the stimulation period and not delivering the neural stimulationsignal for approximately fifty seconds of the stimulation period.
 8. Themethod of claim 6, wherein the predetermined duty cycle is less thanapproximately 25%.
 9. The method of claim 6, wherein the predeterminedduty cycle is within a range between approximately 10% and 20%.
 10. Themethod of claim 1, further comprising adjusting a stimulation intensityfor stimulating the vagus nerve.
 11. The method of claim 10, wherein theneural stimulation signal includes a train of pulses, and adjusting theintensity includes adjusting at least one of amplitude, frequency, orpulse width of a train of pulses.
 12. The method of claim 10, whereinadjusting the stimulation intensity includes adjusting the stimulationschedule, and avoiding physiological habituation includes limitingintensity adjustments of the stimulation schedule.
 13. The method ofclaim 1, wherein the vagal stimulation therapy includes a therapyselected from a heart failure therapy, a hypertension therapy, or aremodeling therapy.
 14. The method of claim 1, further comprisingsensing heart rate and delivering myocardial pacing based on sensedheart rate.
 15. The method of claim 1, further comprising monitoring forphysiological habituation, wherein monitoring includes sensing heartrate to detect physiological habituation, the method further comprisingadjusting the stimulation schedule to avoid further physiologicalhabituation to stimulating the vagus nerve.
 16. A method for deliveringa heart failure therapy in a patient with a vagus nerve, comprising:stimulating the vagus nerve and avoiding physiological habituation tostimulating the vagus nerve, wherein stimulating the vagus nerveincludes using a neural stimulation signal to simultaneously stimulateboth afferent axons and efferent axons in the vagus nerve using a neuralstimulation signal, the neural stimulation signal having a frequency ofapproximately 20 Hz, a pulse width of approximately 300 microseconds,and a duty cycle between 10% and 20% for a stimulation period ofapproximately 1 minute, and wherein avoiding physiological habituationincludes scheduling stimulation of the vagus nerve for the heart failuretherapy using a programmable value for a therapy duration to control atherapy period or a programmable value for an intermittent neuralstimulation parameter associated with on/off timing for stimulating thevagus nerve.
 17. The method of claim 16, further comprising sensingheart rate, wherein stimulating the vagus nerve according to thestimulation schedule includes stimulating the vagus nerve independent ofsensed heart rate.
 18. The method of claim 17, further comprisingmonitoring for physiological habituation using the sensed heart rate todetect physiological habituation, the method further comprisingadjusting the stimulation schedule to avoid further physiologicalhabituation to stimulating the vagus nerve.
 19. The method of claim 17,further comprising delivering myocardial pacing based on the sensedheart rate.
 20. The method of claim 16, wherein using the neuralstimulation signal includes incorporating a passive recharge betweenstimulation pulses.
 21. The method of claim 16, wherein stimulating thevagus nerve includes delivering monophasic stimulation pulses.
 22. Themethod of claim 16, further comprising delivering a first train ofmonophasic pulses of a first polarity, followed by a second train ofmonophasic pulses of a second polarity opposite to the first polarity.23. The method of claim 22, further comprising separately adjustingstimulation parameters for the first and second trains of monophasicpulses to control undesired side effects while maintaining a desiredtherapeutic effect.
 24. The method of claim 16, wherein stimulating thevagus nerve includes delivering biphasic stimulation pulses.
 25. Themethod of claim 24, wherein the biphasic stimulation pulses have a firstphase with a first polarity and a second phase with a second polarityopposite the first polarity, the method further comprising separatelyadjusting stimulation parameters for the first and second phases tocontrol undesired side effects while maintaining a desired therapeuticeffect.
 26. The method of claim 24, wherein stimulating the vagus nerveincludes using a bipolar electrode configuration to stimulate the vagusnerve.
 27. The method of claim 24, wherein stimulating the vagus nerveincludes using a current source pulse output circuit to stimulate thevagus nerve.
 28. The method of claim 27, wherein stimulating the vagusnerve includes delivering stimulation pulses within a pulse amplitudebetween approximately 1.5 mA and approximately 2.0 mA.